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Researchers follow AI path to safer senolytic compounds

Researchers follow AI path to safer senolytic compounds
Senolytic performance of oleandrin and periplocin. a Cell survival assay measuring the senolytic effect in OIS. The panels show a representative crystal violet staining of tissue culture dishes of confluent senescent IMR90 ER:RAS and control IMR90 ER:STOP cells cultured with 100 nM 4OHT, and treated with 10 nM oleandrin, ouabain and periplocin, and DMSO as vehicle control for 72 h. b Cell survival by quantification of the crystal violet staining of the experiment shown in a, as described in “Methods” section. Data represented as individual data points, and bars and error bars representing the mean ± SEM of 12 independent experiments. Statistical analysis was performed using a one-way ANOVA (Tukey’s test) for multiple comparisons. c Cell survival assay measuring the senolytic effect in replicative senescence. Graphs representing the cell survival by quantification of the crystal violet staining of confluent cultures of IMR90 cells at passage 27 (replicative senescence) and IMR90 cells at passage 13 (control) treated with 10 nM oleandrin, ouabain and periplocin, and DMSO as vehicle control for 72 h (related to Supplementary Fig. 9b). Data represented as individual data points, and bars and error bars representing the mean ± SEM of 12 independent experiments. Statistical analysis was performed using a one-way ANOVA (Tukey’s test) for multiple comparisons. d Caspase 3/7 activity assay in control IMR90 ER:STOP and senescent IMR90 ER:RAS cells cultured in media containing 100 nM 4OHT, and treated during 35 h with 10 nM oleandrin, ouabain and periplocin, and DMSO as vehicle control. The panels show representative fluorescent images of caspase 3/7 positive cells (lower panels) and brightfield images (upper panels) of the same field for cell scoring. Percentage of green fluorescent cells per condition is indicated in the panel figures. Representative data of one of two independent experiments. Scale bars represent 100 μm. ns not significant, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Source data are provided as a Source Data file. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-39120-1

Researchers from the University of Edinburgh, Scotland, and the University of Cantabria, Spain, have teamed up to develop an AI trained to discover senolytic medicinal chemistry in familiar compounds.

In the paper, "Discovery of senolytics using ," published in Nature Communications, the researchers detail the efforts to search over 4,300 scientifically described compounds for the right chemical makeup to address .

Cellular senescence is what happens when a cell stops multiplying. This can be from age, where a cell may self-determine that there are too many accumulated mutations to replicate safely or because the cell has been damaged. Senescence plays an essential role in limiting tumor progression by not allowing damaged or mutated cells to proliferate.

The body can tolerate having a few non-participating senescent cells in a tissue. Accumulating high levels of senescent cells with age is associated with various forms of disease—osteoarthritis, lung disease, Alzheimer's, dementia and cancer.

The used 58 previously identified senolytics and 2,465 compounds known to have no senolytic effects to train the AI. After sufficient training, the AI was introduced to libraries containing 4,340 FDA-approved or clinical-stage compounds.

Three senolytic compounds identified in the study are found in herbal medicines. Testing on revealed that all three, ginkgetin, periplocin and oleandrin, were able to remove senescent cells without damaging healthy cells.

One of the three stood out from the others, oleandrin, as the most promising. Oleandrin is a compound in the class of cardiac glycosides which are often used as a heart medication to increase during and in the treatment of hypotension and arrhythmias.

The leading cardiac glycoside compound in use currently is ouabain, known to have relatively high toxicity and is a common cause of poisoning. In fact, ouabain is a crucial component of poison arrows used by Maasai warriors in Kenya.

Oleandrin showed a greater senolytic performance over ouabain, functioning at a low nanomolar range, inhibiting its canonical target and activating its senolytic pathway with higher efficacy. Oleandrin did not affect the viability of normal cells at the tested concentrations, all indicating promising senolytic potential.

Cardiotoxicity is still a concern with oleandrin. The researchers suggest that being used directly on the site of damaged tissue as a localized senolytic therapy might make it an impactful treatment while reducing offsite risks, and are currently assessing such local administration of senolytics for osteoarthritis.

In a parallel effort, the researchers show that ex-vivo senolytics perfusion of human transplant livers preserves tissue architecture and regenerative capacity during cold storage.

The study used existing data to uncover previously unknown knowledge. While the actual research findings offer an exciting new compound to test in overcoming cellular senescence, it is also another example of the beneficial contribution AI can make in the hands of researchers.

More information: Vanessa Smer-Barreto et al, Discovery of senolytics using machine learning, Nature Communications (2023). DOI: 10.1038/s41467-023-39120-1

Journal information: Nature Communications

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